P1043: EFFICACY AND SAFETY OF TRAMETINIB IN ADULTS WITH LANGERHANS CELL HISTIOCYTOSIS AND ERDHEIM-CHESTER DISEASE
Authors: Vitalii Latyshev, Irina Kostina, Alla Kovrigina, Elena Lukina
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are histiocytic diseases characterized by tissue damage due to infiltration with monocyte-derived cells and inflammatory microenvironment. In 2016 both diseases were re-classified in the same group (“L”) due to common recurrent mutations and activation of MAPK-pathway. Different treatment options are available for LCH and ECD, including chemotherapy, anti-cytokine drugs and MAPK-inhibitors. However, there is limited data for MEK-inhibitors, particularly trametinib, in treatment of adults with LCH and ECD. Aims: To evaluate efficacy and safety of trametinib monotherapy in adults with LCH and ECD (“L” - group histiocytosis). Methods: A retrospective study was performed in 10 patients with LCH, ECD or mixed disease (LCH+ECD). Two patients were treatment-naive, 3/10 previously received interferon-alpha or sirolimus, the other five had been treated with chemotherapy. All patients received trametinib at a starting dose of 1 mg/day. Efficacy was evaluated by size changes of all measurable lesions that were detected by CT-scan or MRI. Complete response (CR) was defined as no signs or symptoms of the disease and no detectable lesions by MRI and/or CT-scan. Partial response (PR) was defined as detectable disease with at least 20% reduction of lesions. Results: Ten patients were included with a median age of 39 years (range 28 - 58) and median follow up time of 15 months (range 10 - 31). In 3/8 patients (37,5%) complete response was achieved with non-detectable disease. Other 5/8 (62,5%) had a partial response. Two patients had non-measurable forms of disease – pulmonary involvement only and kidney infiltrates. Both of them had a clinical improvement after trametinib initiation. None of the patients had a progressive disease during trametinib treatment. Adverse events (AE) were observed in 8/10 patients. The most common AE was a skin rash in 6/8 (75%) patients. For all AE’s severity was grade 2 or less. In 5/8 (62,5%) patients AE resolved after dose reduction without efficacy impairment. - № Diagnosis Gender Age Final trametinib dose Adverse events Previous therapy Follow up time, months Best response 1 ECD Male 33 Cycles 1 mg for 21 days than 7 days wash-out Skin rash, periorbital edema Interferon-alpha 2b 29 PR 2 ECD Female 38 1mg/day Skin rash Methylprednisolone, cyclophosphamide 28 PR 3 LCH and ECD Female 37 1 mg EOD Periorbital edema Prednisolone, cyclophosphamide, prospidine, vincristine, cytarabine, interferon, lenalidomide 31 PR 4 LCH Female 54 Cycles 1 mg for 25 days than 5 days wash-out Arthralgias, myalgias Vinblastine, prednisolone, vemurafenib, radiotherapy 19 CR 5 LCH Female 42 1 mg EOD Skin rash Sirolimus 18 N/A 6 ECD Male 46 1mg/day Skin rash, hypertension Nephrostomy only 12 N/A 7 LCH Male 40 1mg/day none Vinblastine, prednisolone, methotrexate, 6-MP, cladribine 11 CR 8 LCH Female 28 1mg/day Skin rash, fluid retention Treatment-naïve 10 PR 9 LCH Male 30 1mg/day none Vinblastine, etoposide, prednisolone 10 PR 10 LCH Female 58 0,5 mg/day Hypertension, skin rash, CPK elevation, myalgia Interferon-alpha 2b, radiotherapy 10 CR Summary/Conclusion: Trametinib is a promising and effective drug for monotherapy in adults with LCH or ECD. Despite only three patients having a complete response, trametinib gives opportunity to control disease with an acceptable toxicity profile. It is worth noting that response to trametinib was non-inferior in patients with previous chemotherapy and even in chemo-resistant patients. Further investigations and prospective trials are required to determine an optimal dosage regimen in adults with “L”-group histiocytosis. Keywords: Mitogen-activated protein kinase (MAPK), Langerhans Cell Histiocytosis, MEK